4-Substituted pyrazoles

ABSTRACT

Pyrazoles of the formula ##STR1## wherein R is hydrogen, alkyl, aryl, aralkyl, trifluoromethyl or a heterocycle; 
     R 1  is aryl or aralkyl unsubstituted or substituted by halo, trifluoromethyl, alkyl, alkoxy or nitro; or a halo-substituted alkylthio moiety; 
     R 2  is lower alkyl; phenyl; or benzyl; 
     R 3  is aryl unsubstituted or substituted by alkyl, alkenyl, alkoxy, halo, trifluoromethyl, trifluoromethoxy, mono- or di-alkylamino, nitro, cyano, carboxamido, sulphonamido or SO n  -alkyl; phenyl having fused thereto a 5- to 7-membered isocyclic or heterocyclic ring, said heterocyclic ring having 1 or 2 oxygen or sulphur heteroatoms; or pyridyl; and 
     R 4  is unsubstituted or substituted carboacyl or sulphonyl; 
     Are useful for their diuretic, saluretic, antihypertensive and antithrombotic properties.

CROSS-REFERENCE

This is a division of Ser. No. 693,970 filed June 8, 1976.

The present invention is concerned with pyrazoles, processes for theirproduction, pharmaceutical compositions wherein said compounds are theactive agents and to methods of effecting diuresis and saluresis inhumans and animals, treating hypertension in humans and animals andtreating thromboses in humans and animals utilizing said compounds.

It is known that pyrazole derivatives are useful as antipyretics,analgesics and antiphlogistics (see G. Erhart and H. Ruschig,Arzneimittel [Medicaments], Volume 1, page 148 (1972)).

In U.S. Ser. Nos. 521,906; 638,517, 637,861; 515,448, now U.S. Pat. No.3,950,528; 459,467, now U.S. Pat. No. 3,949,083; 610,150, now U.S. Pat.No. 4,032,646; 549,408, now U.S. Pat. No. 4,018,890; 633,601, now U.S.Pat. No. 4,045,571; 633,636; 461,285, now U.S. Pat. No. 3,952,008;543,664; 578,516, now U.S. Pat. No. 3,992,404; 631,946, now U.S. Pat.No. 4,056,533; 632,165, now U.S. Pat. No. 4,000,294; 619,891; and582,773, now U.S. Pat. No. 5,053,621; pyrazolones and pyrazoles aredisclosed which are useful for their diuretic, saluretic andantihypertensive properties. The compounds of the present inventiondiffer structurally from the compounds of said applications; inparticular, by the nature of the 5-position substituent, and, in part,by the nature of the group which links the 1-position ring nitrogen withthe substituent at the 1-position.

More particularly, the present invention is concerned with pyrazoles ofthe formula ##STR2## wherein R is hydrogen, alkyl, especially loweralkyl, trifluoromethyl, aryl especially of 6 to 10 carbon atoms, aralkylespecially of 6 to 10 carbon atoms in the aryl moiety and 1 to 4 carbonatoms in the alkyl moiety particularly benzyl, or a heterocyclepreferably of 5 to 7 members;

R¹ is aryl preferably of 6 to 10 carbon atoms unsubstituted orsubstituted by 1 to 3 of the same or different substituents selectedfrom the group consisting of alkyl alkenyl preferably lower alkyl andespecially of 1 to 4 carbon atoms, alkoxy especially lower alkoxy andpreferably of 1 to 4 carbon atoms, halo especially fluoro, chloro andbromo, trifluoromethyl, trifluoromethoxy, cyano and nitro; aralkylespecially of 6 to 10 carbon atoms in the aryl moiety and 1 to 4 carbonatoms in the alkyl moiety unsubstituted or substituted by 1 to 3 of thesame or different substituents selected from the group consisting ofalkyl preferably lower alkyl, alkenyl and especially of 1 to 4 carbonatoms, alkoxy especially lower alkoxy and preferably of 1 to 4 carbonatoms, halo especially fluoro, chloro and bromo, trifluoromethyl andnitro; or haloalkylthio especially of 1 to 4 carbon atoms in the alkylmoiety and 1 to 3 halo atoms;

R² is lower alkyl; phenyl; or benzyl;

R³ is aryl especially of 6 to 10 carbon atoms unsubstituted orsubstituted by 1 to 3 of the same or different substituents selectedfrom the group consisting of alkyl especially lower alkyl and preferablyof 1 to 4 carbon atoms, alkenyl especially lower alkenyl and preferablyof 2 to 4 carbon atoms, alkoxy especially lower alkoxy and preferably of1 to 4 carbon atoms, halo especially fluoro, chloro and bromo,trifluoromethyl, trifluoromethoxy, mono- or di-alkylamino especiallylower alkylamino and preferably of 1 to 4 carbon atoms in the alkylmoiety, nitro, cyano, carboxamido, sulphonamido and SO_(n) -alkylwherein n is 0 to 2; phenyl having fused thereto a 5- to 7-memberedisocyclic or heterocyclic ring, said heterocyclic ring having 1 or 2oxygen or sulphur heteroatoms; or pyridyl; and

R⁴ is a substituted carboacyl or sulphonyl moiety especially of theformula R⁵ CO wherein R⁵ is lower alkyl; lower alkoxy; haloalkyl of 1 to4 carbon atoms in the alkyl moiety and 1 to 3 halo atoms; cycloalkyl of5 to 7 carbon atoms; lower alkylthio; haloalkoxy of 1 to 4 carbon atomsin the alkoxy moiety and 1 to 3 halo atoms; haloalkylthio of 1 to 4carbon atoms in the alkyl moiety and 1 to 3 halo atoms; loweralkoxy(lower alkyl); mono- or di-lower alkylamino(lower alkyl); phenylunsubstituted or substituted by 1 to 3 substituents selected from thegroup consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4carbon atoms, halo, trifluoromethyl, trifluoromethoxy, nitro, cyano,SO_(n) -alkyl of 1 to 4 carbon atoms in the alkyl moiety and n is 0 to2, SO_(n) --CF₃ wherein n is 0 to 2, carbonamido and sulphonamido;phenyl having fused thereto a 5- to 7-membered heterocyclic ring having1 or 2 oxygen or sulphur atoms; or a 5- to 7-membered heterocyclic ringunsubstituted or substituted by alkyl of 1 to 4 carbon atoms, halo ornitro; or R⁶ SO₂ wherein R⁶ is lower alkyl; cycloalkyl of 5 to 7 carbonatoms; or phenyl substituted by 1 or 2 substituents selected from thegroup consisting of alkyl of 1 to 4 carbon atoms, halo, trifluoromethyl,trifluoromethoxy, nitro, cyano and trifluoromethylsulphonyl.

The compounds of formula (I) contain an asymmetric carbon atom and theracemates can, of course, be resolved into the optical antipodes. Eitherthe racemates or the antipodes or their salts can be administered as theactive agent.

The pyrazoles of formula (I) of the present invention are produced when5-pyrazolone derivatives of the formula ##STR3## wherein R, R¹, R² andR³ are as above defined, are reacted with acid derivatives, preferablywith carboxylic acid or carbonic acid derivatives which contain theappropriate unsubstituted or substituted carboacyl moiety or with asulphonic acid derivative which contains the appropriate substituted orunsubstituted sulphonyl moiety. These may be represented by the formula##STR4## wherein X is a moiety which is eliminated under the conditionsof the reaction, such as halo, a 5-membered heterocyclic azole ring, analkyl moiety which is bonded to the carbonyl carbon atom via an oxygenor sulphur atom or a phenyl moiety unsubstituted or substituted by 1 or2 nitro moieties or an acyloxy moiety; and Y is R⁵ wherein R⁵ is asabove defined;

or by the formula

    Z--SO.sub.2 --X'                                           (IV)

wherein X' is halo; and Z is R⁶ wherein R⁶ is as above defined;

either in the presence or absence of inert organic solvents and basicmaterials such as alkali metal hydroxides and carbonates or alkalineearth metal hydroxides and carbonates or organic bases such astriethylamine or pyridine, at a temperature of from about -20° C. to+150° C.

The optical antipodes of the compounds according to the presentinvention are prepared in accordance with methods known from theliterature (compare, for example, Houben-Weyl, IV/2, pages 509 et seq.)by interaction of the compound according to the present invention with achiral medium such as, for example, by recrystallization from anoptically active solvent or by chromatography on a chiral carriersubstance or by reaction of the optically pure 5-pyrazolone derivativesof the formula (II) with the appropriate carboxylic acid derivatives,carbonic acid derivatives or sulphonic acid derivatives of the formulae(III) and (IV).

According to one embodiment of the present invention

R is hydrogen, lower alkyl, trifluoromethyl, aryl of 6 to 10 carbonatoms, aralkyl of 6 to 10 carbon atoms in the aryl moiety and 1 or 2carbon atoms in the alkyl moiety, or a 5- to 7-membered heterocyclicmoiety;

R¹ is a haloalkylthio of 1 to 4 carbon atoms in the alkyl moiety and 1to 3 halo atoms; aryl of 6 to 10 carbon atoms unsubstituted orsubstituted by 1 or 2 of the same or different substituents selectedfrom the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, trifluoromethyl,trifluoromethoxy, nitro and cyano; or aralkyl of 6 to 10 carbon atoms inthe aryl moiety and 1 or 2 carbon atoms in the alkyl moietyunsubstituted or substituted by 1 or 2 of the same or differentsubstituents selected from the group consisting of alkyl of 1 to 4carbon atoms, alkenyl of 2 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, halo, trifluoromethyl, trifluoromethoxy, nitro and cyano;

R² is lower alkyl, phenyl or benzyl;

R³ is aryl of 6 to 10 carbon atoms unsubstituted or substituted by 1 to3 of the same or different substituents selected from the groupconsisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbonatoms, alkoxy of 1 to 4 carbon atoms, halo, trifluoromethyl,trifluoromethoxy, mono- or di-alkylamino of 1 to 4 carbon atoms in eachalkyl moiety, nitro, cyano, carboxamido, sulphonamido and SO_(n) -alkylof 1 to 4 carbon atoms in the alkyl moiety and wherein n is 0 to 2;phenyl having fused thereto a 5- to 7-membered isocyclic or heterocyclicring, said heterocyclic ring having 1 or 2 oxygen or sulphurheteroatoms; or pyridyl; and

R⁴ is R⁵ CO wherein R⁵ is lower alkyl, cycloalkyl of 5 to 7 carbonatoms, halo(lower alkyl), lower alkoxy, lower alkylthio, halo(loweralkoxy), halo(lower alkylthio), lower alkoxy(lower alkyl), mono- ordi(lower alkylamino), phenyl substituted by 1 to 3 substituents selectedfrom the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1to 4 carbon atoms, halo, trifluoromethyl, trifluoromethoxy, nitro,cyano, carboxamido, sulphonamido, SO_(n) -(lower alkyl) wherein n is 0to 2, and SO_(n) --CF₃ wherein n is 0 to 2; phenyl having fused theretoa 5- to 7-membered isocyclic or heterocyclic ring, said heterocyclicring having 1 or 2 oxygen or sulphur heteroatoms; or a 5- to 7-memberedheterocyclic ring unsubstituted or substituted by alkyl of 1 to 4 carbonatoms, halo or nitro; or

R⁴ is R⁶ SO₂ wherein R⁶ is lower alkyl, cycloalkyl of 5 to 7 carbonatoms or phenyl substituted by 1 or 2 substituents selected from thegroup consisting of alkyl of 1 to 4 carbon atoms, halo, trifluoromethyl,trifluoromethoxy, nitro and CF₃ SO₂.

According to another embodiment of the present invention

R is alkyl of 1 to 4 carbon atoms, trifluoromethyl, aryl of 6 to 10carbon atoms, aralkyl of 6 to 10 carbon atoms in the aryl moiety and 1or 2 carbon atoms in the alkyl moiety, or a 5- to 7-memberedheterocyclic moiety;

R¹ is haloalkylthio; aryl of 6 to 10 carbon atoms unsubstituted orsubstituted by 1 or 2 of the same or different substituents selectedfrom the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluoro, chloro, bromo,trifluoromethyl, trifluoromethoxy, nitro and cyano; or aralkyl of 6 to10 carbon atoms in the aryl moiety and 1 or 2 carbon atoms in the alkylmoiety unsubstituted or substituted by 1 or 2 of the same or differentsubstituents selected from the group consisting of alkyl of 1 to 4carbon atoms, alkenyl of 2 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, nitroand cyano;

R² is alkyl of 1 to 4 carbon atoms; phenyl or benzyl;

R³ is aryl of 6 to 10 carbon atoms unsubstituted or substituted by 1 to3 of the same or different substituents selected from the groupconsisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbonatoms, alkoxy of 1 to 4 carbon atoms, fluoro, chloro, bromo,trifluoromethyl, trifluoromethoxy, mono- or di-alkylamino of 1 to 4carbon atoms in each alkyl moiety, nitro, cyano, carboxamido,sulphonamido and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkylmoiety and wherein n is 0 to 2; phenyl having fused thereto a 5- to7-membered isocyclic or heterocyclic ring, said heterocyclic ring having1 or 2 oxygen or sulphur heteroatoms; or pyridyl; and

R⁴ is R⁵ CO wherein R⁵ is alkyl of 1 to 4 carbon atoms, cycloalkyl of 5to 7 carbon atoms, haloalkyl of 1 to 4 carbon atoms in the alkyl moiety,lower alkoxy, alkylthio of 1 to 4 carbon atoms in the alkyl moiety,haloalkylthio of 1 to 4 carbon atoms in the alkyl moiety, alkoxyalkyl of1 to 4 carbon atoms in the alkoxy and in the alkyl moieties, mono- ordi-alkylamino of 1 to 4 carbon atoms in the alkyl moiety, phenylsubstituted by 1 to 3 substituents selected from the group consisting ofalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluoro,chloro, bromo, trifluoromethyl, trifluoromethoxy, nitro, cyano,carboxamido, sulphonamido, SO_(n) -alkyl of 1 to 4 carbon atoms in thealkyl moiety wherein n is 0 to 2, and SO_(n) -- CF₃ wherein n is 0 to 2;phenyl having fused thereto a 5- to 7-membered isocyclic or heterocyclicring, said heterocyclic ring having 1 or 2 oxygen or sulphurheteroatoms; or a 5- to 7-membered heterocyclic ring unsubstituted orsubstituted by alkyl of 1 to 4 carbon atoms, fluoro, chloro, bromo ornitro; or

R⁴ is R⁶ SO₂ wherein R⁶ is alkyl of 1 to 4 carbon atoms, cycloalkyl of 5to 7 carbon atoms or phenyl substituted by 1 or 2 substituents selectedfrom the group consisting of alkyl of 1 to 4 carbon atoms, fluoro,chloro, bromo, trifluoromethyl, trifluoromethoxy, nitro and CF₃ SO₂.

According to another embodiment of the present invention

R is hydrogen, alkyl of 1 to 4 carbon atoms, trifluoromethyl, phenyl orbenzyl;

R¹ is chloroalkylthio of 1 to 4 carbon atoms in the alkyl moiety and 1to 3 chloro atoms; phenyl unsubstituted or substituted by 1 or 2 of thesame or different substituents selected from the group consisting ofalkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkoxy of1 to 4 carbon atoms, fluoro, chloro, bromo, trifluoromethyl,trifluoromethoxy, nitro and cyano; or benzyl unsubstituted orsubstituted by 1 or 2 of the same or different substituents selectedfrom the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 2to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluoro, chloro, bromo,trifluoromethyl, trifluoromethoxy, nitro and cyano;

R² is alkyl of 1 to 4 carbon atoms;

R³ is phenyl substituted by 1 or 2 of the same or different substituentsselected from the group consisting of alkyl of 1 to 8 carbon atoms,alkenyl of 2 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms,cycloalkyl of 5 to 7 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms,fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, nitro, cyano,di-alkylamino of 1 to 4 carbon atoms in each alkyl moiety, carboxamido,sulphonamido or carboxamido or sulphonamido wherein 1 or both of thehydrogen atoms are substituted by 1 or 2 alkyl moieties of 1 to 4 carbonatoms, or wherein said alkyl moieties together with the nitrogen atom towhich they are attached form a 5- to 7-membered heterocyclic ring, saidring containing nitrogen as the only heteroatom or said ring alsocontaining oxygen as a heteroatom, and SO_(n) -alkyl of 1 to 4 carbonatoms in the alkyl moiety wherein n is 0 or 2; phenyl having fusedthereto a saturated or unsaturated 5- to 7-membered isocyclic orheterocyclic ring, said heterocyclic ring having an oxygen or sulphurheteroatom; naphthyl; or pyridyl.

According to another embodiment of the present invention

R³ is phenyl substituted by 1 or 2 of the same or different substituentsselected from the group consisting of methyl, chloro, fluoro ortrifluoromethyl; or tetramethylenephenyl.

According to another embodiment of the present invention

R⁴ is alkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety;alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety;haloalkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety and 1 to 3halo atoms; alkoxyalkylcarbonyl of 1 to 6 carbon atoms in the alkoxy andalkyl moieties; benzoyl nuclear substituted by 1 or 2 substituentsselected from the group consisting of alkyl of 1 to 4 carbon atoms,halo, trifluoromethyl, trifluoromethoxy and nitro, or by 1trifluoromethylsulphonyl; dialkylaminoalkylcarbonyl of 1 to 4 carbonatoms in each of the alkyl moieties; pyrrylcarbonyl; thienylcarbonyl;halothienylcarbonyl; furylcarbonyl; halofurylcarbonyl;pyrazolylcarbonyl; alkylpyrazolylcarbonyl of 1 to 4 carbon atoms in thealkyl moiety; imidazolylcarbonyl; alkylimidazolylcarbonyl of 1 to 4carbon atoms in the alkyl moiety; thiazolylcarbonyl;nitrothiazolylcarbonyl; oxyzolylcarbonyl; isoxazolylcarbonyl;alkylisoxazolylcarbonyl of 1 to 4 carbon atoms in the alkyl moiety;halopicolinylcarbonyl; nicotinylcarbonyl; halonicotinylcarbonyl;pyridazinylcarbonyl; pyrimidinylcarbonyl; pyrazinylcarbonyl;alkylpiperazinylcarbonyl of 1 to 4 carbon atoms in the alkyl moiety;dihydrofurylcarbonyl; tetrahydrofurylcarbonyl;tetrahydropyridylcarbonyl; alkylpiperadylcarbonyl of 1 to 4 carbon atomsin the alkyl moiety; tetrahydropyranylcarbonyl;tetrahydrothiopyranylcarbonyl; thiadiazolylcarbonyl; morpholinocarbonyl;or phenylsulphonyl substituted by 1 or 2 substituents selected from thegroup consisting of alkyl of 1 to 4 carbon atoms, halo and nitro, or by1 trifluoromethylsulphonyl moiety.

According to another embodiment of the present invention

R is hydrogen, alkyl of 1 to 3 carbon atoms, trifluoromethyl or benzyl;

R¹ is phenyl unsubstituted or substituted by alkyl of 1 to 3 carbonatoms, alkoxy of 1 to 3 carbon atoms, trifluoromethyl, trifluoromethoxy,halo, methyl, thio, nitro or cyano;

R² is methyl or ethyl;

R³ is phenyl substituted by 2 halo atoms; or tetramethylenephenyl; and

R⁴ is acetyl; benzoyl nuclear substituted by 1 or 2 substituentsselected from the group consisting of alkyl of 1 or 2 carbon atoms,alkoxy of 1 or 2 carbon atoms, fluoro, chloro, trifluoromethyl, nitroand cyano; or furylcarbonyl;

According to another embodiment of the present invention

R⁴ is acetyl; benzoyl nuclear substituted by 1 or 2 substituentsselected from the group consisting of methyl, methoxy, fluoro, chloro,trifluoromethyl, nitro and cyano; or furylcarbonyl.

According to another embodiment of the present invention

R is alkyl of 1 to 3 carbon atoms, trifluoromethyl, or phenyl;

R¹ is phenyl substituted by alkyl of 1 or 2 carbon atoms, alkoxy of 1 or2 carbon atoms, chloro or fluoro; or benzyl;

R² is methyl or ethyl;

R³ is phenyl substituted by 1 or 2 of the same or different substituentsselected from the group consisting of alkyl of 1 or 2 carbon atoms,chloro, fluoro and trifluoromethyl; naphthyl; tetramethylenephenyl; orpyridyl; and

R⁴ is R⁵ CO wherein R⁵ is alkyl of 1 to 4 carbon atoms, haloalkyl of 1to 4 carbon atoms in the alkyl moiety and 1 to 3 halo atoms selectedfrom the group consisting of chloro and fluoro; alkoxy of 1 to 4 carbonatoms; mono- or di-alkylamino of 1 to 4 carbon atoms in the each alkylmoiety; phenyl substituted by 1 to 3 substituents selected from thegroup consisting of alkyl of 1 or 4 carbon atoms, alkoxy of 1 or 4carbon atoms, fluoro, chloro and trifluoromethylsulphonyl; or a 5- to7-membered heterocyclic ring unsubstituted or substituted by alkyl of 1or 4 carbon atoms, fluoro, chloro or nitro; or

R⁴ is R⁶ SO₂ wherein R⁶ is phenyl substituted by 1 or 2 substituentsselected from the group consisting of alkyl of 1 or 4 carbon atoms,chloro, fluoro, nitro and trifluoromethylsulphonyl.

According to another embodiment of the present invention

R⁴ is R⁵ CO wherein R⁵ is alkyl of 1 or 2 carbon atoms, haloalkyl of 1or 2 carbon atoms in the alkyl moiety and 1 to 3 halo atoms selectedfrom the group consisting of chloro and fluoro; alkoxy of 1 or 2 carbonatoms; mono- or di-alkylamino of 1 or 2 carbon atoms in each alkylmoiety; phenyl substituted by 1 to 3 substituents selected from thegroup consisting of alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2carbon atoms, fluoro, chloro and trifluoromethylsulphonyl; or a 5- to7-membered heterocyclic ring unsubstituted or substituted by alkyl of 1or 2 carbon atoms, fluoro, chloro or nitro.

According to another embodiment of the present invention

R is alkyl of 1 or 2 carbon atoms or pyridyl;

R¹ is phenyl;

R² is methyl;

R³ dichlorophenyl or tetramethylenephenyl; and

R⁴ acetyl, methylbenzoyl, methoxybenzoyl, chlorobenzoyl, fluorobenzoyl,dichlorobenzoyl or furylcarbonyl.

Depending on the nature of the starting materials used, the synthesis ofthe compounds according to the present invention can be represented bythe following equation in which3-methyl-4-phenyl-1-(α-methyl-4-chlorobenzyl)-5-pyrazolone and acetylchloride have been chosen as examples: ##STR5##

The 5-pyrazolone derivatives of formula (II), used as startingmaterials, have not been previously disclosed but can be prepared inaccordance with methods known from the literature (compare, for example,L. Knorr, Ber. dtsch. Chem. Ges. 16, 2,597 (1883)), by reactinghydrazines of the formula (V) with β-carbonyl-fatty acid derivatives ofthe formula ##STR6## wherein R, R¹, R² and R³ are as above defined,

The following compounds are representative of the 5-pyrazolones offormula (II):3-methyl-4-phenyl-1-(α-methyl-3-fluorobenzyl)-5-pyrazolone,3-methy-4-phenyl-1-(α-methyl-4-fluorobenzyl)-5-pyrazolone,3-methyl-4-phenyl-1-(α-methyl-3-chlorobenzyl)-5-pyrazolone,3-methyl-4-phenyl-1-(α-methyl-4-chlorobenzyl)-5-pyrazolone,3-ethyl-4-phenyl-1-(α-methyl-4-bromobenzyl)-5-pyrazolone,3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone,4-(4-chlorophenyl)-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone,4-(4-methylphenyl)-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone,4-(3,4-dichlorophenyl)-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone,3-methyl-4-phenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-5-pyrazolone,3-phenyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone,3-phenyl-4-phenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-5-pyrazolone,3-phenyl-4-phenyl-1-(α-(naphthyl-(2))-ethyl)-5-pyrazolone and3-phenyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazolone.

In formula (III) ##STR7## Y is preferably R⁵ according to theembodiments set forth above.

X is preferably is halo, such as fluoro, chloro or bromo, especiallychloro, or a 5-membered heterocyclic azole ring, such as imidazole,pyrazole, 1,3,4-triazole, especially imidazole, wherein the heterocyclicring is bonded to the carbonyl carbon atom in formula (III) via anitrogen, or is R⁷ which is bonded to the carbonyl atom in formula (III)via an oxygen atom or a sulphur atom and which is a straight or branchedchain alkyl moiety of 1 to 4 carbon atoms, phenyl unsubstituted orsubstituted by 1 or 2 nitro moieties or an acyloxy moiety of the formula##STR8## wherein Y' has the same meaning as Y but need not be identialto Y so that mixed anhydrides may also be employed.

The starting materials used in accordance with formula (III) are knownfrom the literature and can be prepared according to methods known fromthe literature (compare, for example, Houben Weyl, Methoden derorganischen Chemie (Methods of Organic Chemistry), VIII, page 101(1952), Weygand/Hilgetag, Org. Chemische Experimentierkunst (The Art ofExperimentation in Organic Chemistry), page 246, 4th edition, 1970,Verlag J. A. Barth, Leipzig).

The following starting materials are representative of those which maybe used according to the present invention: acetyl chloride, propionylchloride, isopropionyl chloride, acetic anhydride, trifluoroaceticanhydride, propionic anhydride, butyric anhydride, β-methoxy-propionicacid chloride, phenylacetic acid chloride, phenoxyacetic acid chloride,4-chlorophenoxyacetic acid chloride, ethoxycarbonyl acetate,phenoxycarbonyl acetate, benzoyl chloride, benzoic anhydride,thiobenzoic acid S-phenyl ester, ethoxycarbonyl benzoate, N¹-benzoylimidazolide, 4-chlorobenzoyl chloride, 4-fluorobenzoyl chloride,4-trifluoromethylbenzoyl chloride, 4-trifluoromethylsulphonylbenzoylchloride, 4-trifluoromethoxybenzoyl chloride,(4-trifluoromethylthio)-benzoyl chloride, 3,4-dichlorobenzoyl chloride,3-chloro-4-methylbenzoyl chloride, 4-nitrobenzoyl chloride,4-methoxybenzoyl chloride, chlorocarbonic acid ethyl ester,chlorocarbonic acid isobutyl ester, chlorocarbonic acid benzyl ester,chlorocarbonic acid β-methoxyethyl ester, chlorocarbonic acidβ-phenoxyethyl ester, carbonic acid diethyl ester, carbonic aciddi-n-butyl ester, pyrocarbonic acid diethyl ester, N,N-dimethylcarbamicacid chloride, N,N-diethylcarbamic acid chloride, N,N-di-n-butylcarbamicacid chloride, pyridine-2-carboxylic acid chloride, nicotinic acidchloride, isonicotinic acid chloride, thiophene-2-carboxylic acidchloride, thiophene-3-carboxylic acid chloride, furane-2-carboxylic acidchloride, furane-3-carboxylic acid chloride, pyrazole-4-carboxylic acid4-nitrophenyl ester, the anhydride of pyrazole-3-carboxylic acid andcarbonic acid monoethyl ester,4-methyl-imidazole-5-carboxylic acidchloride, N¹ -methyl-imidazole-4-carboxylic acid chloride,isoxazole-3-carboxylic acid chloride, 5-methyl-isoxazole-3-carboxylicacid chloride, isoxazole-4-carboxylic acid chloride,5-methyl-isoxazole-4-carboxylic acid chloride, isoxazole-5-carboxylicacid chloride, 3-methylisoxazole-5-carboxylic acid chloride,isothiazole-3-carboxylic acid chloride, N-methylpyrrolidine-4-carboxylicacid chloride, ethoxycarbonyl-pyrrolidine-2-carboxylate,N-chlorocarbonyl-piperidine, N-methyl-N'-chlorocarbonylpiperazine andN-chlorocarbonyl-morpholine.

In formula (IV)

    z--so.sub.2 --x'                                           (iv)

z is R⁶ according to the embodiments set forth above and X' is halo,especially chlorine.

The starting materials used according to formula (IV) are known from theliterature or can be prepared according to methods known from theliterature (compare, for example, Weygand/Hilgetag, Org. ChemischeExperimentierkunst (The Art of Experimentation in Organic Chemistry),page 691, page 704 and page 645, 4th edition, 1970, Verlag J. A. Barth,Leipzig).

The following starting materials are representative of those materialswhich may be used according to the present invention: methanesulphonicacid chloride, ethanesulphonic acid chloride, butanesulphonic acidchloride, benzenesulphonic acid chloride, p-toluenesulphonic acidchloride, 4-chlorobenzenesulphonic acid chloride,3-chlorobenzenesulphonic acid chloride, 4-fluorobenzenesulphonic acidchloride, 3,4-dichlorobenzenesulphonic acid chloride and3-chloro-4-methylbenzenesulphonic acid chloride.

Suitable diluents are all inert solvents. These preferentially includehydrocarbon atoms such as benzene, toluene and xylene,halogenohydrocarbons, such as methylene chloride, chloroform, carbontetrachloride and chlorobenzene, ethers, such as tetrahydrofurane,dioxane and glycol dimethyl ether, amides, such as dimethylformamide,dimethylacetamide, N-methylpyrrolidone and hexamethylphosphoric acidtriamide, sulphoxides, such as dimethylsulphoxide, sulphones, such assulpholane, and bases, such as pyridine, picoline, collidine, lutidineand quinoline.

Suitable basic auxiliaries are inorganic and organic bases. Thesepreferentially include alkali metal hydroxides and alkali metalcarbonates, such as sodium hydroxide or potassium carbonate, andtert.-amines, such as triethylamine or pyridine.

The reaction temperatures can be varied within a wide range. In general,the reaction is carried out at between -10° and 150° C., preferablybetween 0° and 100° C. It is carried out under normal pressure, but canalso be carried out under a higher pressure in closed vessels.

In carrying out the process according to the invention, one mol of the5-pyrazolone derivative is reacted with 1 to 5 mols of the carboxylicacid derivative, carbonic acid derivative or sulphonic acid derivativein an inert diluent, if appropriate in the presence of molar amounts ofa basic auxiliary, such as triethylamine or pyridine. The compoundsaccording to the invention, which in most cases are obtained in acrystalline form after removing the diluent, can easily be prepared in apure form by recrystallization from a suitable solvent.

The following compounds are representative of those of the presentinvention:5-acetoxy-3-trifluoromethyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-acetoxy-3-methyl-4-phenyl-1-(α-methyl-3-chloro-4-methyl)-pyrazole,5-acetoxy-3-ethyl-4-phenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-pyrazole,5-acetoxy-3-methyl-4-(4-chlorophenyl)-1-(α-naphthyl-(2)-ethyl)-pyrazole,5-acetoxy-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-acetoxy-4-phenyl-1-(α-methyl-4-fluorobenzyl)-pyrazole,5-acetoxy-3,4-diphenyl-1-(α-methyl-3,4-ditrifluoromethylbenzyl)-pyrazole,5-propionyloxy-4-phenyl-1-(α-propyl-3,4-dichlorobenzyl)-pyrazole,5-propionyloxy-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-propionyloxy-3-isopropyl-4-(4-chlorphenyl)-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-n-butyryloxy-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-trimethylacetoxy-3-methyl-4-phenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-pyrazole,5-isovaleryloxy-3-methyl-4-phenyl-1-(α-methyl-3,4-difluorobenzyl)-pyrazole,5-trifluoroacetoxy-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-trifluoroacetoxy-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-trifluoroacetoxy-3,4-diphenyl-1-(α-methyl-3,4-ditrifluoromethylbenzyl)-pyrazole,5-chloroacetoxy-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-chloroacetoxy-3,4-diphenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-pyrazole,5-dichloroacetoxy-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-dichloroacetoxy-3,4-diphenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-pyrazole,5-(3-chloropropionyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorbenzyl)-pyrazole,5-(2-methoxyacetoxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(2-dimethylaminoacetoxy)-3-ethyl-4-phenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-pyrazole,5-(2-fluorobenzoyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(3-fluorobenzoyloxy)-3-isopropyl-4-(4-chlorophenyl)-1-(α-ethyl-3,4-difluorobenzylpyrazole,5-(3-chlorobenzoyloxy)-3-methyl-4-benzyl-1-(α-methyl-3-trifluoromethylbenzyl)-pyrazole,5-(4-trifluoromethylsulphonylbenzoyloxy)-3-methyl-4-benzyl-1-(α-naphthyl-(2)-ethyl)-pyrazole,5-(pyrryl-(2)-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(pyrryl-(3)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-pyrazole,5-(thienyl-(2)-carbonyloxy)-3-methyl-4-phenyl-1-(α-pyridyl-(2)-ethyl)-pyrazole,5-(thienyl-(3)-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-difluorobenzyl)-pyrazole,5-(furyl-(2)-carbonyloxy)-3-(4-chlorophenyl)-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(furyl-(3)-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-4-fluorobenzyl)pyrazole,5-(pyrazolyl-(3)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(pyrazolyl-(4)-carbonyloxy)-3-methyl-4-(4-chlorophenyl)-1-(α-methyl-4-chlorobenzyl)-pyrazole,5-(4-methyl-pyrazolyl-(3)-carbonyloxy)-3-n-propyl-4-phenyl-1-(α-pyridyl-(3)-ethyl)-pyrazole,5-(4-methylimidazolyl-(2)-carbonyloxy)-3-ethyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(imidazolyl-(2)-carbonyloxy)-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(thiazolyl-(2)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(5-nitrothiazolyl-(2)-carbonyloxy)-3-methyl-4-(3-chlorophenyl)-1-(.alpha.-naphthyl-(2)-ethyl)-pyrazole,5-(oxazolyl-(4)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(oxazolyl-(5)-carbonyloxy)-3-methyl-4-benzyl-1-(α-methyl-4-fluorobenzyl)-pyrazole,5-(isoxazolyl-(3)-carbonyloxy)-3-phenyl-4-benzyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(isoxazolyl-(4)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-4-chlorobenzyl)-pyrazole,5-(5-methylisoxazolyl-(3)-carbonyloxy)-3-trifluoromethyl-4-benzyl-1-(.alpha.-methyl-3,4-dichlorobenzyl)-pyrazole,5-(5-methylisoxazolyl-(3)-carbonyloxy)-3-ethyl-4-benzyl-1-(α-methyl-3-chloro-4-methylbenzyl)-pyrazole,5-(3-fluoropicolinoyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(nicotinoyloxy)-3-n-propyl-4-(4-methylphenyl)-1-(α-methyl-3,4-difluorobenzyl)-pyrazole,5-(4)fluoronicotinoyloxy)-4-benzyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(dihydrofuryl-(2)-carbonyloxy)-3-(4-chlorophenyl)-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(tetrahydrofuryl-(2)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(1-methyl-1,4,5,6-tetrahydropyridyl-(3)-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(1-methylpiperidyl-(2)-carbonyloxy)-3-methyl-4-(2-methylphenyl)-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(1-methylpiperidyl-(3)-carbonyloxy)-3-methyl-4-(4-methylphenyl)-1-(.alpha.-methyl-4-chlorobenzyl)-pyrazole,5-(1-methylpiperidyl-(4)-carbonyloxy)-3-methyl-4-(3-methyl-4-chlorophenyl)-1-(α-methyl-4-fluorobenzyl)pyrazole,5-(tetrahydropyranyl-(2)-carbonyloxy)-3-methyl-4-(3-methylphenyl)-1-(.alpha.-methyl-3,4-dichlorobenzyl)-pyrazole,5-(tetrahydrothiopyranyl-(2)-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(1,2,3-thiadiazolyl-(4)-carbonyloxy)-3-methyl-4-(4-methylphenyl)-1-(.alpha.-methyl-3,4-dichlorobenzyl)-pyrazole,5-(morpholinocarbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(isonicotinoyloxy)-3-isopropyl-4-(3-chlorophenyl)-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(2,6-dichloroisonicotinoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(2,6-dichloroisonicotinoyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(pyridazinyl-(3)-carbonyloxy)-3-phenyl-4-benzyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(pyridazinyl-(4)-carbonyloxy)-3-isopropyl-4-benzyl-1-(α-methyl-4-fluorobenzyl)-pyrazole,5-(pyrimidinyl-(4)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(pyrimidinyl-(2)-carbonyloxy)-3-ethyl-4-(p-methoxyphenyl)-1-(α-methyl-4-fluorobenzyl)-pyrazole,5-(pyrimidinyl-(5)-carbonyloxy)-3-n-propyl-4-(p-fluorophenyl)-1-(α-methyl-4-chlorobenzyl)-pyrazole,5-(pyrazinyl-(2)-carbonyloxy)-3-ethyl-4-phenyl-1-(α-ethyl-3,4-tetramethylenebenzyl)-pyrazole,5-(4-methyl-piperazinyl-(1)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(1-ethylpiperidyl-(2)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(1-ethylpiperidyl-(2)-carbonyloxy)-3,4-diphenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazole,5-(1-ethylpiperidyl-(3)-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-4-chlorobenzyl)-pyrazole,5-(1-ethylpiperidyl-(3)-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(3-methylphenylsulphonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3-chlorobenzyl)-pyrazole,5-(3,4-dimethylphenylsulphonyloxy)-3-methyl-4-(4-chlorophenyl)-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole,5-(3-chlorophenylsulphonyloxy)-1-methyl-4-phenyl-1-(pyridyl-(3)-ethyl)-pyrazole,5-(2-fluorophenylsulphonyloxy)-3,4-diphenyl-1-(α-methyl-3-trifluoromethylbenzyl)-pyrazole,5-(4-trifluoromethylsulphenylphenylsulphonyloxy)-3-methyl-4-phenyl-1-(.alpha.-naphthyl-(2)-ethyl)-pyrazole,5-(fluorophenylsulphonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazole,5-(4-fluorophenylsulphonyloxy)-3-methyl-4-(4-methylphenyl)-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazoleand5-(3,4-dinitrophenylsulphonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3-chloro-4-methylbenzyl)-pyrazole.

The pharmaceutical compositions of the present invention contain a majoror minor amount e.g. 0.1 to 99.5%, preferably 0.5 to 90%, of activeingredient as above defined in combination with a pharmaceuticallyacceptable nontoxic inert diluent or carrier, the carrier comprising oneor more solid, semi-solid or liquid diluent, filler and formulationadjuvant which is nontoxic, inert and pharmaceutically acceptable. Suchpharmaceutical compositions are preferably in dosage unit form; i.e.,physically discrete units containing a predetermined amount of the drugcorresponding to a fraction or multiple of the dose which is calculatedto produce the desired therapeutic response. The dosage units cancontain one, two, three, four or more single doses or, alternatively,one half, third or fourth of a single dose. A single dose preferablycontains an amount sufficient to produce the desired therapeutic effectupon administration at one application of one or more dosage unitsaccording to a predetermined dosage regimen, usually a whole, half,third or quarter of the daily dosage administered once, twice, three orfour times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the dosage will be from0.01 to 500 mg/kg of body weight per day. In some instances a sufficienttherapeutic effect can be obtained at a lower dose, while in others alarger dose will be required.

The preferred daily dose is 0.5 mg to 10 g of active agent.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl cellulose, analginate, gelatin, or polyvinylpyrrolidone, a solution retardant such asparaffin, a resorption accellerator such as a quaternary salt and/or anabsorption agent such as bentonite, kaolin or dicalcium phosphate. Thepowder mixture can be granulated by wetting with a binder such as syrup,starch paste, acacia mucilage or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolishcoating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Non-toxic salts and salt solutions can be added to render the injectionisotonic.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low-melting, water-soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as forexample myristyl palmitate, or mixtures thereof.

While routes of administration include oral, parenteral (i.e.,intramuscular, intraperitoneal and intravenous) and rectal, oral andparenteral administration are particularly preferred.

The preferred daily dose, in the case of parenteral administration, is0.01 to 50 mg/kg, preferably 0.1 to 10 mg/kg of body weight daily; whilefor oral administration the preferred daily dose is about 0.1 to 500mg/kg, preferably 0.5 to 100 mg/kg, of body weight daily.

The preferred pharmaceutical compositions are therefore those in a formsuitable for oral administration, such as tablets and suspensions, andthose suitable for parenteral application, such as solutions andsuspensions, to effect diuresis, saluresis and to treat hypertension byeliminating water and salts and also are useful for the treatment ofprophylaxis of thromboembolic diseases. In addition, the compounds areuseful for the treatment of oedemacious and hypertonic conditions andfor flooding out of toxic substances so that they may be used in thecase of acute kidney failure.

The following formulation is representative of those of the presentinvention: 200 g of5-(4-fluorobenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazoleare ground to a powder which is mixed with 300 g of lactose and 200 g ofpotato starch and, after moistening with an aqueous gelatine solution,the mixture is granulated by passing through a sieve. After drying, 60 gof talc and 5 g of sodium lauryl-sulphate are added. From this mixtureabout 10,000 tablets each containing 20 mg of active compound arepressed.

To demonstrate the antithrombotic action of the compounds according tothe invention, the substance described in Example 1 was administered torats.

The left jugular vein of rats weighing 170 to 180 g was exposed underether narcosis and supercooled to -12° C. for 2 minutes to stimulatethromb formation. The thromb was isolated from the vein 4 hours later,and was weighed. The test animals were given the test preparation intragacanth mucilage immediately before supercooling the wall of theblood vessel. As a result, the protective antithrombotic activity wastested in the first 4 hours after stimulating thromb formation.

The results of the investigations using the compounds according to theinvention are shown in the table which follows:

    ______________________________________                                                              Animals treated                                                               with the com-                                                       Control on                                                                              pound according                                                     animals   to the in-                                                          without   vention (10 mg/                                                     active com-                                                                             kg, administered                                                    pound     orally)                                                 ______________________________________                                        Thromb size in                                                                μg, mean value                                                                           115 ± 12 51 ± 10                                          Number of experi-                                                             ments         14          12                                                  Inhibition in %                                                                              0           56%                                                ______________________________________                                    

The results show that the compounds according to the inventionsignificantly inhibit the formation of venous thrombs.

After a 4 hour period of action, the size of the thrombs has beenreduced by 56%.

The remaining compounds show comparable properties and can therefore beused for the prophylaxis of thrombembolic diseases.

In addition to the inhibiting action on the formation of thrombs, thecompounds according to the invention are also distinguished by a verypowerful thrombolytic action. Thrombotic deposits already formed areredispersed under the influence of the compound. Correspondingthrombolytic effects were hitherto only achievable by repeatedintravenous administration of toxic fibrinolytics such as streptokinaseand urokinase, while the compounds according to the invention areadministered orally and only once daily.

The following nonlimitative examples more particularly illustrate thepresent invention.

EXAMPLE 15-(4-Fluorobenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole##STR9##

0.1 mol (34.7 g) of3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone wasdissolved in 300 ml of absolute dioxane. After adding 15 ml oftriethylamine, 0.11 mol (17 g) of p-fluorobenzoyl chloride in dioxanewas added dropwise. After heating for several hours under reflux, thereaction batch was worked up as follows.

The organic phase obtained after cooling, and after filtering off theprecipitates of crystalline salt was concentrated, the residue was takenup in methylene chloride, and the methylene chloride solution wasrepeatedly extracted by shaking with water and was dried with magnesiumsulphate.

The oily residue obtained after concentrating the methylene chloridephase became crystalline on trituration with methanol. The crystallinecrude product was recrystallized from ethyl acetate. Melting point:112°-114° C.; yield: 76% of theory.

The following products were obtained analogously to the proceduredescribed in Preparation Example 1:

EXAMPLE 2 ##STR10##

5-(4-Chlorobenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone andp-chlorobenzoyl chloride.

Melting point: 107°-109° C. (ethanol); yield: 83% of theory.

EXAMPLE 3 ##STR11##

5-(2-Chlorobenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone and2-chlorobenzoyl chloride.

Melting point: 123°-125° C. (ethanol); yield: 89% of theory.

EXAMPLE 4 ##STR12##

5-(4-Methylbenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone and4-methylbenzoyl chloride.

Melting point: 108°-110° C. (ethyl acetate); yield: 86% of theory.

EXAMPLE 5 ##STR13##

5-(4-Methoxybenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone and4-methoxy-benzoyl chloride.

Melting point: 121°-123° C. (ethyl acetate); yield: 78% of theory.

EXAMPLE 6 ##STR14##

5-(Furyl-2-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone andfurane-2-carboxylic acid chloride.

Melting point: 80°-82° C. (ethyl acetate); yield: 53% of theory.

EXAMPLE 7 ##STR15##

5-Acetoxy-3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-pyrazole wasobtained from3-methyl-4-phenyl-1-(α-methyl-3,4-dichlorobenzyl)-5-pyrazolone andacetyl chloride.

Melting point: 93°-95° C. (ether); yield: 55% of theory.

EXAMPLE 8 ##STR16##

5-(4-Methylbenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazolewas obtained from3-methyl-4phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazolone and4-methylbenzoyl chloride.

Melting point: 109°-110° C. (ethanol); yield: 78% of theory.

EXAMPLE 9 ##STR17##

5-(4-Methoxybenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazolone and4-methoxybenzoyl chloride.

Melting point: 136°-138° C. (ethanol); yield: 92% of theory.

EXAMPLE 10 ##STR18##

5-(4-Chlorobenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylene-benzyl)-5-pyrazoloneand 4-chlorobenzoyl chloride.

Melting point: 114°-115° C. (ethanol/ether); yield: 84% of theory.

EXAMPLE 11 ##STR19##

5-(2,5-Dichlorobenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazolone and2,5-dichlorobenzoyl chloride.

Melting point: 152°-154° C. (ethanol): yield: 81% of theory.

EXAMPLE 12 ##STR20##

5-(4-Fluorobenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazolone and4-fluorobenzoyl chloride.

Melting point: 133°-135° C. (ethanol); yield: 79% of theory.

EXAMPLE 13 ##STR21##

5-(4-Methoxybenzoyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazolone and4-methoxybenzoyl chloride.

Melting point: 136°-138° C. (ethanol); yield: 84% of theory.

EXAMPLE 14 ##STR22##

5-(Furyl-2-carbonyloxy)-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazolone andfurane-2-carboxylic acid chloride.

Melting point: 94°-96° C. (methanol); yield: 81% of theory.

EXAMPLE 15 ##STR23##

5-Acetoxy-3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-pyrazolewas obtained from3-methyl-4-phenyl-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazolone andacetyl chloride.

Melting point: 66°-68° C. (ether); yield: 52% of theory.

EXAMPLE 16 ##STR24##

5-(4-Chlorobenzoyloxy)-3-methyl-4-(chlorodifluoromethylthio)-1-(α-methyl-3,4-tetramethylene-benzyl-pyrazolewas obtained from3-methyl-4-(chlorodifluoromethylthio)-1-(α-methyl-3,4-tetramethylenebenzyl)-5-pyrazoloneand 4-chlorobenzoyl chloride.

Melting point: 83°-85° C. (ethanol); yield: 89% of theory.

What is claimed is:
 1. A pharmaceutical composition useful for effectingdiuresis and saluresis in humans and animals and for treatinghypertension and thromboses in humans and animals which comprises adiuretically effective amount, a saluretically effective amount, ananti-hypertensively effective amount or an antithrombotically effectiveamount of a compound of the formula ##STR25## wherein R is hydrogen orlower alkyl;R¹ is haloalkylthio of 1 to 4 carbon atoms in the alkylmoiety and 1 to 3 halo atoms; R² is lower alkyl; R³ is aryl of 6 to 10carbon atoms unsubstituted or substituted by 1 to 3 of the same ordifferent substituents selected from the group consisting of alkyl of 1to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms, alkoxy of 1 to 4carbon atoms, halo, trifluoromethyl, trifluoromethoxy, mono- ordi-alkylamino of 1 to 4 carbon atoms in each alkyl moiety, nitro, cyano,carboxamido, sulphonamido and SO_(n) -alkyl of 1 to 4 carbon atoms inthe alkyl moiety and wherein n is 0 to 2; or phenyl having fused theretoa 5- to 7-membered isocyclic ring; and R⁴ is R⁵ CO wherein R⁵ is loweralkyl, cycloalkyl of 5 to 7 carbon atoms, halo (lower alkyl), loweralkoxy, lower alkythio, halo(lower alkoxy), halo(lower alkythio), loweralkoxy(lower alkyl), mono- or di(lower alkylamino), phenyl substitutedby 1 to 3 substituents selected from the group consisting of alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, trifluoromethyl,trifluoromethoxy, nitro, cyano, carboxamido, sulphonamido, SO_(n)-(lower alkyl) wherein n is 0 to 2, and SO_(n) -CF₃ wherein n is 0 to 2or phenyl having fused thereto a 5- to 7-membered isocyclic ring, incombination with a pharmaceutically acceptable carrier.
 2. A compositionaccording to claim 1 whereinR is alkyl of 1 to 4 carbon atoms; and R⁴ isR⁵ CO wherein R⁵ is alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to 7carbon atoms, haloalkyl of 1 to 4 carbon atoms in the alkyl moiety,lower alkoxy, alkylthio of 1 to 4 carbon atoms in the alkyl moiety,haloalkylthio of 1 to 4 carbon atoms in the alkyl moiety, alkoxyalkyl of1 to 4 carbon atoms in the alkoxy and in the alkyl moieties, mono- ordi-alkylamino of 1 to 4 carbon atoms in the alkyl moiety, phenylsubstituted by 1 to 3 substituents selected from the group consisting ofalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluoro,chloro, bromo, trifluoromethyl, trifluoromethoxy, nitro, cyano,carboximido, sulphonamideo, SO_(n) -alkyl of 1 to 4 carbon atoms in thealkyl moiety wherein n is 0 to 2, and SO_(n) --CF₃ wherein n is 0 to 2;or phenyl having fused thereto a 5- to 7-membered isocyclic ring.
 3. Acomposition according to claim 1 whereinR is hydrogen or alkyl of 1 to 4carbon atoms; R¹ is chloroalkylthio of 1 to 4 carbon atoms in the alkylmoiety and 1 to 3 chloro atoms; R² is alkyl of 1 to 4 carbon atoms; R³is phenyl substituted by 1 or 2 of the same or different substituentsselected from the group consisting of alkyl of 1 to 8 carbon atoms,alkenyl of 2 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms,cycloalkyl of 5 to 7 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms,fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, nitro, cyano,dialkylamino of 1 to 4 carbon atoms in each alkyl moiety, carboxamido,sulphonamido or carboxamido or sulphonamido wherein 1 or both of thehydrogen atoms are substituted by 1 or 2 alkyl moieties of 1 to 4 carbonatoms, and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkyl moietywherein n is 0 or 2; or phenyl having fused thereto a saturated 5- to7-membered isocyclic ring.
 4. A composition according to claim 3whereinR³ is tetramethylenephenyl.
 5. A composition according to claim 1whereinR⁴ is alkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety;alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety;haloalkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety and 1 to 3halo atoms; alkoxyalkylcarbonyl of 1 to 6 carbon atoms in the alkoxy andalkyl moieties; benzoyl nuclear substituted by 1 or 2 substituentsselected from the group consisting of alkyl of 1 to 4 carbon atoms,halo, trifluoromethyl, trifluoromethoxy and nitro, or by 1trifluoromethylsulphonyl; or dialkylaminoalkylcarbonyl of 1 to 4 carbonatoms in each of the alkyl moieties.
 6. A composition according to claim1 whereinR is hydrogen or alkyl of 1 to 3 carbon atoms; R² is methyl orethyl; R³ is phenyl substituted by 2 halo atoms; ortetramethylenephenyl; and R⁴ is acetyl; or benzoyl nuclear substitutedby 1 or 2 substituents selected from the group consisting of alkyl of 1or 2 carbon atoms, alkoxy of 1 or 2 carbon atoms, fluoro, chloro,trifluoromethyl, nitro and cyano.
 7. A composition according to claim 6whereinR⁴ is acetyl; or benzoyl nuclear substituted by 1 or 2substituents selected from the group consisting of methyl, methoxy,fluoro, chloro, trifluoromethyl, nitro and cyano.
 8. A compositionaccording to claim 1 whereinR is alkyl of 1 to 3 carbon atoms; R² ismethyl or ethyl; R³ is phenyl substituted by 1 or 2 of the same ordifferent substituents selected from the group consisting of alkyl of 1or 2 carbon atoms, chloro, fluoro and trifluoromethyl; naphthyl; ortetramethylenephenyl; and R⁴ is R⁵ CO wherein R⁵ is alkyl of 1 to 4carbon atoms, haloalkyl of 1 to 4 carbon atoms in the alkyl moiety and 1to 3 halo atoms selected from the group consisting of chloro and fluoro;alkoxy of 1 to 4 carbon atoms; mono- or di-alkylamino of 1 to 4 carbonatoms in each alkyl moiety; or phenyl substituted by 1 to 3 substituentsselected from the group consisting of alkyl of 1 or 4 carbon atoms,alkoxy of 1 or 4 carbon atoms, fluoro, chloro, andtrifluoromethylsulphonyl.
 9. A composition according to claim 8whereinR⁴ is R⁵ CO wherein R⁵ is alkyl of 1 or 2 carbon atoms, haloalkylof 1 or 2 carbon atoms in the alkyl moiety and 1 to 3 halo atomsselected from the group consisting of chloro and fluoro; alkoxy of 1 or2 carbon atoms; mono- or di-alkylamino of 1 or 2 carbon atoms in eachalkyl moiety; or phenyl substituted by 1 to 3 substituents selected fromthe group consisting of alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2carbon atoms, fluoro, chloro and trifluoromethylsulphonyl.
 10. Acomposition according to claim 1 whereinR is alkyl of 1 or 2 carbonatoms; R² is methyl; R³ is dichlorophenyl or tetramethylenephenyl; andR⁴ is acetyl, methylbenzoyl, methoxybenzoyl, chlorobenzoyl,fluorobenzoyl or dichlorobenzoyl.
 11. A composition according to claim 1wherein the compound is ##STR26##
 12. A method of effecting diuresis andsaluresis in humans and animals and treating hypertension in humans andanimals which comprises administering to a human or animal in needthereof a diuretically effecdive amount, a saluretically effectiveamount or an anti-hypertensively effective amount of a compound of theformula ##STR27## wherein R is hydrogen or lower alkyl;R¹ ishaloalkylthio of 1 to 4 carbon atoms in the alkyl moiety and 1 to 3 haloatoms; R² is lower alkyl; R³ is aryl of 6 to 10 carbon atomsunsubstituted or substituted by 1 to 3 of the same or differentsubstituents selected from the group consisting of alkyl of 1 to 4carbon atoms, alkenyl of 2 to 4 carbon atoms, alkoxy of 1 to 4 carbonatoms, halo, trifluoromethyl, trifluoromethoxy, mono- or di-alkylaminoof 1 to 4 carbon atoms in each alkyl moiety, nitro, cyano, carboxamido,sulphonamido and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkylmoiety and wherein n is 0 to 2; or phenyl having fused thereto a 5- to7-membered isocyclic ring; and R⁴ is R⁵ CO wherein R⁵ is lower alkyl,cycloalkyl of 5 to 7 carbon atoms, halo(lower alkyl), lower alkoxy,lower alkylthio, halo(lower alkoxy), halo(lower alkylthio), loweralkoxy(lower alkyl), mono- or di(lower alkylamino), phenyl substitutedby 1 to 3 substituents selected from the group consisting of alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halo, trifluoromethyl,trifluoromethoxy, nitro, cyano, carboxamido, sulphonamido, SO_(n)-(lower alkyl) wherein n is 0 to 2, and SO_(n) --CF₃ wherein n is 0 to2; or phenyl having fused thereto a 5- to 7-membered isocyclic ring, incombination with a pharmaceutically acceptable carrier.
 13. A methodaccording to claim 12 whereinR is alkyl of 1 to 4 carbon atoms; and R⁴is R⁵ CO wherein R⁵ is alkyl of 1 to 4 carbon atoms, cycloalkyl of 5 to7 carbon atoms, haloalkyl of 1 to 4 carbon atoms in the alkyl moiety,lower alkoxy, alkylthio of 1 to 4 carbon atoms in the alkyl moiety,haloalkylthio of 1 to 4 carbon atoms in the alkyl moiety, alkoxyalkyl of1 to 4 carbon atoms in the alkoxy and in the alkyl moieties, mono- ordi-alkylamino of 1 to 4 carbon atoms in the alkyl moiety, phenylsubstituted by 1 to 3 substituents selected from the group consisting ofalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, fluoro,chloro, bromo, trifluoromethyl, trifluoromethoxy, nitro, cyano,carboximido, sulphonamideo, SO_(n) -alkyl of 1 to 4 carbon atoms in thealkyl moiety wherein n is 0 to 2, and SO_(n) --CF₃ wherein n is 0 to 2;or phenyl having fused thereto a 5- to 7-membered isocyclic ring.
 14. Amethod according to claim 12 whereinR is hydrogen or alkyl of 1 to 4carbon atoms; R¹ is chloroalkylthio of 1 to 4 carbon atoms in the alkylmoiety and 1 to 3 chloro atoms; R² is alkyl of 1 to 4 carbon atoms; R³is phenyl substituted by 1 or 2 of the same or different substituentsselected from the group consisting of alkyl of 1 to 8 carbon atoms,alkenyl of 2 to 8 carbon atoms, alkoxy of 1 to 6 carbon atoms,cycloalkyl of 5 to 7 carbon atoms, cycloalkenyl of 5 to 7 carbon atoms,fluoro, chloro, bromo, trifluoromethyl, trifluoromethoxy, nitro, cyano,dialkylamino of 1 to 4 carbon atoms in each alkyl moiety, carboxamido,sulphonamido or carboxamido or sulphonamido wherein 1 or both of thehydrogen atoms are substituted by 1 or 2 alkyl moieties of 1 to 4 carbonatoms, and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkyl moietywherein n is 0 or 2; or phenyl having fused thereto a saturated 5- to7-membered isocyclic ring.
 15. A method according to claim 12 whereinR³is tetramethylenephenyl.
 16. A method according to claim 12 whereinR⁴ isalkylcarbonyl of 1 to 6 carbon atoms in the alkyl moiety; alkoxycarbonylof 1 to 6 carbon atoms in the alkoxy moiety; haloalkylcarbonyl of 1 to 6carbon atoms in the alkyl moiety and 1 to 3 halo atoms;alkoxyalkylcarbonyl of 1 to 6 carbon atoms in the alkoxy and alkylmoieties; benzoyl nuclear substituted by 1 or 2 substituents selectedfrom the group consisting of alkyl of 1 to 4 carbon atoms, halo,trifluoromethyl, trifluoromethoxy and nitro, or by 1trifluoromethylsulphonyl; or dialkylaminoalkylcarbonyl of 1 to 4 carbonatoms in each of the alkyl moieties.
 17. A method according to claim 12whereinR is hydrogen or alkyl of 1 to 3 carbon atoms; R² is methyl orethyl; R³ is phenyl substituted by 2 halo atoms; ortetramethylenephenyl; and R⁴ is acetyl; or benzoyl nuclear substitutedby 1 or 2 substituents selected from the group consisting of alkyl of 1or 2 carbon atoms, alkoxy of 1 or 2 carbon atoms, fluoro, chloro,trifluoromethyl, nitro and cyano.
 18. A method according to claim 17whereinR⁴ is acetyl; or benzoyl nuclear substituted by 1 or 2substituents selected from the group consisting of methyl, methoxy,fluoro, chloro, trifluoromethyl, nitro and cyano.
 19. A method accordingto claim 12 whereinR is alkyl of 1 to 3 carbon atoms; R² is methyl orethyl; R³ is phenyl substituted by 1 or 2 of the same or differentsubstituents selected from the group consisting of alkyl of 1 or 2carbon atoms, chloro, fluoro and trifluoromethyl; naphthyl; ortetramethylenephenyl; and R⁴ is R⁵ CO wherein R⁵ is alkyl of 1 to 4carbon atoms, haloalkyl of 1 to 4 carbon atoms in the alkyl moiety and 1to 3 halo atoms selected from the group consisting of chloro and fluoro;alkoxy of 1 to 4 carbon atoms; mono- or di-alkylamino of 1 to 4 carbonatoms in each alkyl moiety; or phenyl substituted by 1 to 3 substituentsselected from the group consisting of alkyl of 1 or 4 carbon atoms,alkoxy of 1 or 4 carbon atoms, fluoro, chloro, andtrifluoromethylsulphonyl.
 20. A method according to claim 19 whereinR⁴is R⁵ CO wherein R⁵ is alkyl of 1 or 2 carbon atoms, haloalkyl of 1 or 2carbon atoms in the alkyl moiety and 1 to 3 halo atoms selected from thegroup consisting of chloro and fluoro; alkoxy of 1 or 2 carbon atoms;mono- or di-alkylamino of 1 or 2 carbon atoms in each alkyl moiety; orphenyl substituted by 1 to 3 substituents selected from the groupconsisting of alkyl of 1 or 2 carbon atoms, alkoxy of 1 or 2 carbonatoms, fluoro, chloro and trifluoromethylsulphonyl.
 21. A methodaccording to claim 12 whereinR is alkyl of 1 or 2 carbon atoms; R² ismethyl; R³ is dichlorophenyl or tetramethylenephenyl; and R⁴ is acetyl,methylbenzoyl, methoxybenzoyl, chlorobenzoyl, fluorobenzoyl ordichlorobenzoyl.
 22. A method according to claim 12 wherein the compoundis ##STR28##